The investigation will involve the study of gene probes in a unique resource of 70 families with the familial atypical multiple mole melanoma (FAMMM) syndrome which are in variable stages of extension and documentation. Utilizing 19 of these kindreds, we shall select 54 patients with pathologically verified FAMMM moles, some of whom will have manifested cutaneous malignant melanoma (CMM), and 116 of their first degree relatives (50% risk for FAMMM). Utilizing peripheral blood lymphocytes from which DNA will be obtained, we will perform a linkage study employing a large number of well characterized genetic markers. This will include several hundred variable number tandem repeat (VNTR) markers and the more conventional site polymorphisms, all of which have been under investigation at Dr. White's laboratories of the Howard Hughes Medical Institute at the University of Utah School of Medicine at Salt Lake City. Linkage analysis programs at the center will be employed for this phase of the study. Concurrent with this gene probe investigation, we shall capitalize upon and expand our existing FAMMM resource in order to better comprehend its genetics and natural history in context with dysplastic (atypical) nevi and CMM as well as extra-nonmelanotic forms of cancer. We will study a consecutive series of patients with dysplastic nevi and/or CMM, and their family members. Tissues from patients with atypical moles, CMM, and nonmelanotic cancer will be studied by a cadre of pathologists. Association among moles, CMM, and nonmelanotic cancer will be evaluted. These linkage and clinicopathologic studies will enable us to test hypotheses generated by our group which propose that this cancer-associated genodermatosis is due to an autosomal dominantly inherited pleiotropic gene which, in addition to causing atypical nevi and CMM, also predisposes to a variety of systemic forms of cancer. The full extent of the tumor spectrum remains controversial. Our biostatistical analyses will also take into account and evaluate the frequently neglected problem of possible etiologic and phenotypic heterogeneity within the FAMMM. This investigation is exceedingly important in that the FAMMM appears to be etiologic in a highly significant fraction of the overall malignant melanoma burden. Controversy exists relevant to so-called sporadic forms vs. genetic variants of FAMMM. Because of limitations in identification of the atypical nevus phenotype from both the clinical and dermatopathological standpoints, it is crucial that we develop gene probes of acceptable sensitivity and specificity for genotype. Given the technology available to us, this may lead to the identification of the deleterious gene.